IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell-rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4ϩ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell-rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90 -100%) and a specificity of 92% (95% CI 86 -95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN.

IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that typically manifests as fibro-inflammatory masses that can affect nearly any organ system. Renal involvement by IgG4-RD usually takes the form of IgG4-related tubulointerstitial nephritis, but cases of membranous glomerulonephritis (MGN) have also been described. Here we present a series of 9 patients (mean age at diagnosis 58 years) with MGN associated with IgG4-RD. All patients showed MGN on biopsy, presented with proteinuria (mean 8.3 g/day), and most had elevated serum creatinine (mean 2.2 mg/dl). Seven patients had known extrarenal involvement by IgG4-RD, with 5 patients having concurrent IgG4-related tubulointerstitial nephritis. Immunohistochemical analysis for the phospholipase A2 receptor, a marker of primary MGN, was negative in all 8 biopsies so examined. Six of 7 patients with available follow-up (mean 39 months) were treated with immunosuppressive agents; one untreated patient developed end-stage renal disease and underwent transplantation, without recurrence at 12 years after transplant. All 6 treated patients showed decreased proteinuria (mean 1.2 g/day), and most showed decreased serum creatinine (mean 1.4 mg/dl). Thus, MGN should be included in the spectrum of IgG4-RD and should be suspected in proteinuric IgG4-RD patients. Conversely, patients with MGN and an appropriate clinical history should be evaluated for IgG4-RD.

The severity of renal histopathological findings in patients who underwent nephrectomy for resistant hypertension correlated with an increased prevalence of cardiovascular disease, a greater degree of renal dysfunction and more severe dyslipidaemia. Statin therapy may affect development of intra-renal injury by slowing the progression of fibrosis.

Tumor budding in colorectal carcinoma has been associated with poor outcome in multiple studies, but the absence of an established histologic cutoff for “high” tumor budding, heterogeneity in study populations and varying methods for assessing tumor budding have hindered widespread incorporation of this parameter in clinical reports. We used an established scoring system in a population-based cohort to determine a histologic cutoff for “high” tumor budding and confirm its prognostic significance. We retrieved hematoxylin and eosin-stained sections from 553 incident colorectal carcinoma cases. Each case was previously characterized for select molecular alterations and survival data. Interobserver agreement was assessed between two GI pathologists and a group of four general surgical pathologists. High budding (≥10 tumor buds in a 20× objective field) was present in 32% of cases, low budding in 46% and no budding in 22%. High tumor budding was associated with advanced pathologic stage (p<0.001), microsatellite stability (p=0.005), KRAS mutation (p=0.010) and on multivariate analysis with a greater than two times risk of cancer-specific death (HR=2.57 (1.27, 5.19)). After multivariate adjustment, via penalized smoothing splines, we found increasing tumor bud counts from 5 upward to be associated with an increasingly shortened cancer-specific survival. By this method, a tumor bud count of 10 corresponded to approximately 2.5 times risk of cancer –specific death. The interobserver agreement was good with weighted kappa of 0.70 for two GI pathologists over 121 random cases and 0.72 between all six pathologists for 20 random cases. Using an established method to assess budding on routine histologic stains, we have shown a cutoff of 10 for high tumor budding is independently associated with a significantly worse prognosis. The reproducibility data provide support for the routine widespread implementation of tumor budding in clinical reports.

Background Although C4d deposition in peritubular capillaries has been identified as a strong risk factor for subsequent renal allograft loss, the optimal cut-off for the fraction of peritubular capillaries needed to establish a positive stain in formalin-fixed paraffin-embedded material has not been systematically defined. The objective of this study was to establish the threshold for positive staining that best predicts renal outcome in renal biopsies in a multicenter study in which local and central pathology were compared. Methods Unstained renal biopsy slides were obtained from 296 patients. The percentage of peritubular capillaries staining positively for C4d was detected by immunoperoxidase staining. Results The percentage C4d deposition ranged from 0% to 90% with 44% (129/296) having a positive percentage of C4d staining. The median for positive cases was 25%. Local C4d+ results were reported qualitatively, with 28% recorded as positive for C4d. Using a centrally-determined cut-off of 10%, tests for agreement of local and central C4d staining were fair (Kappa 0.40, 95% CI 0.29-0.51). Raising the centrally-determined cut-off to 25% or 50% did not change the Kappa values (0.44 and 0.41, respectively). By Cox proportional hazards model, C4d positivity (centrally-determined assessment) using a cut-off of 10% was the strongest predictor of time to graft loss (HR 2.66, 95% CI [1.68, 4.21]). Centrally-determined C4d positivity correlated with Banff scores indicative of acute inflammation, but not with scores indicative of fibrosis/atrophy or transplant glomerulopathy. Conclusions Our findings indicate that C4d positivity, defined as ≥10% by immunoperoxidase, is a strong predictor of graft loss.